Anti-hepatocarcinoma effects of 5-fluorouracil encapsulated by galactosylceramide liposomes in vivo and in vitro.

AIM: To study the anti-hepatocarcinoma effects of 5-fluorouracil (5-Fu) encapsulated by galactosylceramide liposomes (5-Fu-GCL) in vivo and in vitro. METHODS: Tumor-bearing animal model and HepA cell line were respectively adopted to evaluate the anti-tumor effects of 5-Fu-GCL in vivo and in vitro. Tumor cell growth inhibition effects of 5-Fu-GCL in vitro were assessed by cell viability assay and MTT assay. In vivo experiment, the inhibitory effects on tumor growth were evaluated by tumor inhibition rate and animal survival days. High performance liquid chromatography was used to detect the concentration-time course of 5-Fu-GCL in intracellular fluid in vitro and the distribution of 5-Fu-GCL in liver tumor tissues in vivo. Apoptosis and cell cycle of tumor cells were demonstrated by flow cytometry. RESULTS: In vitro experiment, 5-Fu-GCL (6.25-100 micromol/L) and free 5-Fu significantly inhibited HepA cell growth. Furthermore, IC50 of 5-Fu-GCL (34.5 micromol/L) was lower than that of free 5-Fu (51.2 micromol/L). In vivo experiment, 5-Fu-GCL (20, 40, 80 mg/kg) significantly suppressed the tumor growth in HepA bearing mice model. Compared with free 5-Fu, the area under curve of 5-Fu-GCL in intracellular fluid increased 2.6 times. Similarly, the distribution of 5-Fu-GCL in liver tumor tissues was significantly higher than that of free 5-Fu. After being treated with 5-Fu-GCL, the apoptotic rate and the proportion of HepA cells in the S phase increased, while the proportion in the G0/G1 and G2/M phases decreased. CONCLUSION: 5-Fu-GCL appears to have anti-hepato-carcinoma effects and its drug action is better than free 5-Fu. Its mechanism is partly related to increased drug concentrations in intracellular fluid and liver tumor tissues, enhanced tumor cell apoptotic rate and arrest of cell cycle in S phase.

Pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes in mice.

AIM: To study the pharmacokinetics and tissue distribution of 5-fluorouracil encapsulated by galactosylceramide liposomes (5-Fu-GCL) in mice. METHODS: The concentration of 5-fluorouracil (5-Fu) in serum was detected by high performance liquid chromatography after 5-Fu-GCL (80, 40, 20 mg/kg) and free 5-Fu (40 mg/kg) were injected intravenously into mice. The tissue distribution of 5-Fu-GCL (40 mg/kg) and free 5-Fu (40 mg/kg) was investigated, and concentration-time profile of the two preparations in the liver were studied. Data were analyzed by 3p97 program. RESULTS: Serum concentration-time curves of 5-Fu-GCL and free 5-Fu conformed to one compartment model of first order absorption. 5-Fu-GCL at 80, 40, and 20 mg/kg had T(1/2Ke) of 25.8+/-4.2, 27.3+/-4.4, and 28.2+/-5.6 min; C0 of 24.9+/-4.9, 17.7+/-3.6, and 11.5+/-2.7 mg/L; and AUC of 990.0+/-45.2,622.5+/-38.3, and 340.4+/-25.6 mg x min x L(-1), respectively. In contrast free 5-Fu at 40 kg/mg had T(1/2Ke) of 15.8+/-2.2 min, C0 of 35.8+/-6.2 mg/L, AUC of 639.0+/-35.9 mg x min x L(-1). The tissue distribution of 5-Fu-GCL in the liver and immune organs was significantly increased, while in heart and kidney it was remarkably decreased. The AUC of 5-Fu-GCL in the liver was 3 times higher than that of free 5-Fu. CONCLUSION: The pharmacokinetics and tissue distribution of 5-Fu-GCL appears to be linear-related and dose-dependent, and exhibits sustained-release and hepatic target characteristics.